Preterm birth is a leading cause of neonatal morbidity and mortality, accounting for 35% of infant healthcare spending and 10% of all childcare spending in the United States. In addition, medical costs from birth to one year of age are 10-fold greater for babies born premature and/or at low-birth weight when compared to those for babies born full-term. The rate of preterm birth has steadily increased by 20% since 1990, with 12.5% of all U.S. births being preterm births. Thus, there is a clear and significant need to understand the biological and molecular mechanisms leading to preterm birth, as well as to improve a physician's ability to predict which women are at risk for preterm delivery.
There are approximately 500,000 preterm births per year in the United States, of which approximately 30-70% are associated with an underlying infectious process. Infection is a major risk factor for pre-term birth after the most consistently identified risks factors, which include: a history of preterm birth, current multi-fetal pregnancy, and some uterine and/or cervical abnormalities. The ability to identify high-risk pregnancies at an early stage will lead to a significant reduction in the incidence of preterm birth and most likely reduce the incidence of fetal demise, decrease the rate of cerebral palsy, and other neuro-developmental delays. By improving our ability to identify those at risk of preterm birth, we also provide for the development of new and more effective treatments for preterm labor.
There is little overlap between the current biomarkers of preterm birth, suggesting that these various biomarkers predict different pathways that lead to preterm birth, and suggesting that the creation of a highly predictive biomarker would be beneficial. Currently, there are a handful of biomarkers which attempt to predict preterm labor in advance in order to prevent preterm delivery. These biomarkers include fetal fibronectin, salivary estriol, decidual proteins, and endocrinelparacrine. Fetal fibronectin and salivary estriol have been examined in some detail, with fetal fibronectin now being made available commercially. The fetal fibronectin test is based on the detection of fetal fibronectin, a fetal-specific glycosylated form of fibronectin. The theory is that increased amounts of fetal fibronectin signal the disturbance of the junction of the fetal membranes and the placental deciduas and therefore predicts delivery. In symptomatic pregnant women, the test has only limited effectiveness (58% sensitivity) to predict preterm delivery before the completion of 37 weeks gestation. The main benefit of the present test is the ability to exclude the possibility of preterm delivery (85% specificity) and to avoid unnecessary interventions. Parturition is comprised of 5 events: (1) membrane rupture; (2) cervical dilation; (3) myometrial contaction; (4) placental separation; and (5) uterine involution. While previously available tests might focus on detection of only a subset of these five events (and thus potentially lead to a heightened likelihood for “false positives” in the detection of a purported increased likelihood of preterm birth conditions), the present invention relates to a novel method for heightened sensitivity (e.g., detection of a unified factor relating to all 5 significant steps in parturition), coupled with a more practical effectiveness to diagnosis and possibly treat or prevent a broader range of potential preterm birth conditions. See, U.S. Pat. Nos. 4,919,889; 5,096,830; 5,223,440; 5,281,522; 5,431,171; 5,468,619; 5,516,702; 5,597,700; 5,641,636; 5,650,394; 5,698,404; 5,783,396; 5,877,029; 5,891,722; 5,968,758; 6,126,597; 6,126,616; 6,140,099; 6,149,590; 6,267,722; 6,312,393; 6,394,952; 6,544,193; 6,556,977; 6,610,480; 6,678,669; 6,867,051; 6,875,567; 6,936,476; 7,041,063; 7,191,068; 7,228,295; 7,270,970; 7,403,805; 7,488,585; 7,524,636; 7,528,133; 7,654,957; 7,709,272; 7,756,559; 7,809,417; 7,811,279; 7,863,007; 7,943,294; 8,060,195; 8,068,990; 8,114,610; 8,133,859; 8,160,692; 8,366,640; 8,372,581; 8,501,688; 8,517,960; 8,552,364; U.S. Pat. Pub. Nos. 20010023419; 20010025140; 20010053876; 20020031513; 20020046054; 20020049389; 20030004906; 20030099651; 20030105731; 20030113319; 20030139687; 20040014063; 20040039297; 20040039298; 20040078219; 20040100376; 20040197930; 20040241752; 20040266025; 20050101841; 20050131287; 20050163771; 20050260683; 20050277912; 20060008923; 20060014302; 20060024722; 20060024723; 20060024724; 20060024725; 20060024757; 20060040337; 20060166242; 20060166295; 20060204532; 20060240495; 20060240498; 20070016074; 20070128589; 20070142718; 20070161125; 20080009552; 20080090759; 20080254479; 20080299594; 20090036761; 20090055099; 20090058072; 20090068692; 20090081206; 20090171234; 20090227036; 20090299212; 20100008911; 20100017143; 20100029006; 20100093621; 20100145180; 20100311190; 20100318025; 20110028807; 20110040161; 20110065139; 20110090048; 20110159533; 20110166070; 20110184254; 20110237972; 20110312927; 20110312928; 20120009609; 20120040356; 20120046261; 20120052595; 20120082598; 20120157422; 20120196285; 20120202740; 20120238469; 20120238894; 20120270747; 20130029957; 20130053670; 20130071865; 20130171672; 20130177485; and 20130225922, each of which is expressly incorporated herein by reference.
Measurement of changes in Lipocalin-type prostaglandin D2 synthase (L-PGDS) levels in human cervicovaginal fluid has been suggested as a possible indicator of membrane rupture during pregnancy. Shiki Y, Shimoya K, Tokugawa Y, Kimura T, Koyama M, Azuma C, Murata Y, Eguchi N, Oda H, Urade Y 2004 Changes of lipocalin-type prostaglandin D synthase level during pregnancy. J Obstet Gynaecol Res 30:65-70 (37), each of which is expressly incorporated herein by reference.
Rachel J. A. Helliwell, Jeffrey A. Keelan, Keith W. Marvin, Linda Adams, Maxwell C. Chang, Ashmit Anand, Timothy A. Sato, Simon O'Carroll, Tinnakom Chaiworapongsa, Roberto J. Romero, and Murray D. Mitchell, “Gestational Age-Dependent Up-Regulation of Prostaglandin D Synthase (PGDS) and Production of PGDS-Derived Antiinflammatory Prostaglandins in Human Placenta”, The Journal of Clinical Endocrinology & Metabolism, vol. 91 no. 2 pp. 597-606 (Feb. 1, 2006), each of which is expressly incorporated by reference, discuss that The two isoforms of PGDS (L-PGDS and H-PGDS) immunolocalized to distinct regions of human term and preterm gestational tissues. In placental villous tissues, specific labeling for L-PGDS was identified in the syncytiotrophoblast layer of both preterm and term placenta, with prominent staining of the apical membrane. At term, cytoplasmic syncytial staining was readily apparent in the syncytium, giving rise to a characteristic beaded appearance. Similarly, strong H-PGDS immunolabeling was observed in the syncytial layer of the preterm placenta. However, cellular localization of H-PGDS appeared to change with gestational age, and by term, immunoreactive H-PGDS was mainly localized to cells lining the villous capillaries, with little or no labeling observed in the syncytium. Labeling was completely absent in the corresponding negative controls in which primary antibody was preincubated with a 10-fold excess of blocking peptide or was omitted completely. In gestational membranes collected from both preterm and term pregnancies, strong immunolabeling for L-PGDS was observed in the cells of all tissues, including amnion epithelial, reticular, chorionic trophoblast, and decidual cells. In contrast, only very weak labeling of the gestational membranes was observed for H-PGDS. No labeling was observed in the corresponding negative controls. No significant staining of infiltrating leukocytes was apparent, although on some slides occasional cells positive for L- or H-PGDS were visualized among maternal blood cells. There was no statistical difference in the net amount of H-PGDS in any tissue as a result of the onset of labor at term or the presence of intrauterine infection preterm. Immunoreactive L-PGDS was undetectable in gestational tissues. L-PGDS mRNA was detectable in amnion, choriodecidual, and villous placental samples There was no significant effect of preterm intrauterine infection or term labor on the level of expression of L-PGDS mRNA. L-PGDS mRNA levels were significantly higher in the choriodecidua and placenta than in the amnion. There was no significant difference in the level of expression between the choriodecidua and placenta. The expression of H-PGDS mRNA was detectable in all three tissues, with no significant effect of preterm intrauterine infection or labor at term. Analyzing the combined data for each tissue revealed that the relative expression of H-PGDS mRNA was lowest in the amnion and choriodecidua, with a significantly higher level of expression in the villous placenta.
See also, Olson D M, Ammann C, “Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour”, Front Biosci.; 12:1329-43 (Jan. 1, 2007), and Pirianov G, Waddington S N, Lindstrom T M, Terzidou V, Mehmet H, Bennett P R, “The cyclopentenone 15-deoxy-delta12,14-prostaglandin J2 delays lipopolysaccharide-induced preterm delivery and reduces mortality in the newborn mouse”, Endocrinology 150(2):699-706 (Epub 2008 Oct. 9, February 20909), each of which is expressly incorporated herein by reference.
U.S. Pat. No. 7,399,596 and US 20070020609, expressly incorporated herein by reference, discusses using L-PGDS levels to predict pregnancy-induced hypertension. See also, U.S. Pat. Nos. 7,902,373, 7,794,953, 7,582,643, 7,314,727, 7,109,044, 6,790,635, 6,605,705, 6,410,583, 20110021599, 20100323911, 20100251394, 20080233597, 20080227113, 20070196864, 20070003992, 20040038314, 20030190678, each of which is expressly incorporated herein by reference.
Specific DP1/DP2 agonists and antagonists are available, e.g., BW245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl-hydantoin), AS702224, TS-022, 15R-methyl-PGD2, 13-14-dihydro-15-keto-PGD2, AM156, AM206, L-745870, 15R-PGD(2), MK-0524, BWA868C, BW24-SC, BAY-u3405, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), 11-deoxy-11-methylene PGD2, G06983 (PKCα,Δ,ε,δ), G06976 (PKCα), GF10923X (PKCα,Δ,ε), LY333531 (PKC β), SB203580 (p38MAPK), SB203580, CD200, FGF18, GPRC5D, GPR49, LRRC15, Serpin A, CDT6, BMP2, LHX2, THBS1, MYCN, NR4A2, MEST, TM4SF1, CRLF1, TNFRSF12A, SELENBP1, GPR161, HEPH, FZD7, and CLIC4, CCL18, Col11A1, Col3A1, CD4, Cd1a, FCER1A, HLA-C, HLA-DPA1, IGF1, GPR105, PDGFRL, ADRA2A, CCL19, CORN, 16-phenoxy-17,18,19,20-tetranor PGD2 N-cyclopropylamide, 16-phenoxy-17,18,19,20-tetranor PGD1 N-cyclopropylmethylamide, 16-phenoxy-17,18,19,20-PGD1N-(1,3-dihydroxypropan-2-yl))amide; 17-phenyl-18,19,20-trinor PGD2 N-cyclopropylamide, 17-phenyl-18,19,20-trinor PGD1 N-cyclopropylmethylamide, 17-phenyl-18,19,20-trinor PGD2N-(1,3-dihydroxypropan-2-yl))amide; 16-(3-chlorophenyl)-17,18,19,20-tetranor PGD2 N-cyclopropylamide, 16-(3-chlorophenyl)-17,18,19,20-tetranor PGD1 N-cyclopropylmethylamide, 6-(3-chlorophenyl)-17,18,19,20-tetranor PGD1 N-(1,3-dihydroxypropan-2-yl))amide, (Z)-isopropyl 7-((R)-2-((R)-3-hydroxy-5-phenylpentyl)-5-oxocyclopent-2-enyl)hept-5-enoate, (Z)-isopropyl 7-((R)-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-5-oxo-cyclopent-2-enyl)hept-5-enoate, (Z)—N-ethyl-7-((R)-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-5-oxocyclopent-2-enyl)hept-5-enamide, (Z)—N-ethyl-7-((R)-2-((S,E)-3-hydroxy-5-phenylpent-1-enyl)-5-oxocyclopen-t-2-enyl)hept-5-enamide, (Z)-7-((R)-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-5-oxocyclopent-2-enyl)hept-5-enoic acid, (Z)-7-((R)-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-5-oxocyclopent-2-enyl)-N-methylhept-5-enamide, (Z)-7-((R)-2-((R,E)-4-(3-chlorophenoxy)-3-hydroxybut-1-enyl)-5-oxocyclope-nt-2-enyl)hept-5-enoic acid, (Z)-isopropyl 7-((R)-2-((R,E)-4-(3-chlorophenoxy)-3-hydroxybut-1-enyl)-5-oxocyclopent-2-enyl)hept-5-enoate, (Z)-7-((R)-2-((R,E)-4-(3-chlorophenoxy)-3-hydroxybut-1-enyl)-5-oxocyclopent-2-enyl)-N-methylhept-5-enamide or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or metabolite thereof. These agents may be used alone or in combination, and may be administered concurrently or sequentially. See also, 2011/0144160, 2011/0130453, 2011/0112134, 2011/0098352, 2011/0098302, 2011/0071175, 2011/0060026, 2011/0034558, 2011/0028717, 2011/0021599, 2011/0021573, 2011/0002866, 2010/0330077, each of which is expressly incorporated herein by reference.